1. Field of the Invention
The present invention relates to polyacrylate-based pressure-sensitive adhesives for medical purposes which are used in the production of adhesive plasters, transdermal therapeutic systems (TTSs) and other devices adhering to the skin. The invention especially relates to active substance-containing pressure sensitive adhesives for use in transdermal therapeutic systems. The invention furthermore comprises the use of such pressure sensitive adhesives for the production of devices which, for therapeutic or diagnostic purposes, are durably secured to the skin.
2. Description of the Related Art
Pressure sensitive adhesives are highly viscous, elastic adhesives which, after one has exerted a short, slight pressure thereon, immediately and durably adhere to the substrate concerned, e.g. the skin. It is for this reason that they are called “pressure sensitive” adhesives (=PSA). On account of their viscoelasticity they are capable of conforming very well to the skin of different areas of the body and are therefore suited to a multitude of medical application purposes. In addition they can in most cases be removed again from the substrate at a later point in time, without thereby destructing the substrate. In transdermal therapeutic systems, pressure sensitive adhesives can have both the function of an active substance reservoir in the form of a polymer matrix, into which the active substance has been introduced, and the function of the pressure-sensitive adhesive attachment of the systems on the skin.
The presently most frequently utilised pressure sensitive adhesives are based on synthetic rubber polymers, polyacrylates or silicones. Pressure sensitive adhesives based on synthetic rubber polymers generally require the use of so-called “tackifiers”, e.g. tackifying resins based on colophony derivatives, to be able to achieve a sufficient bioadhesive adhesion to the human skin. By contrast thereto, pressure-sensitive adhesives based on polyacrylate polymers or silicones are—because of their chemical structure and the physicochemical properties resulting therefrom—self-adhesive without the necessity of adding tackifying substances.
With pressure sensitive adhesives based on synthetic rubber polymers and tackifying resins, it is frequently observed that they possess, insufficient skin tolerance, whereas the problem of skin tolerance in polyacrylate or silicone pressure sensitive adhesives has for the most part been solved.
However, the presently known polyacrylate polymers and silicones do not meet all of the demands made on medical high-performance adhesives, for instance for use in transdermal therapeutic systems. Above all, it is to be emphasized in this respect that the adhesion of the pressure sensitive adhesive to the skin must be maintained even under extreme conditions, for instance in extreme climatic conditions or in the case of increased and enduring moistness of the skin, e.g. caused by sweating heavily. Increased formation of skin moisture can also be brought about by the occlusion effect caused by a TTS applied to the skin.
In addition, in particular for silicone adhesives, there has as yet no satisfactory solution been found to the problem of “cold flow”. With respect to TTSs or pressure sensitive adhesive plasters, this term is understood to refer to punched plaster surfaces flowing in lateral directions at their edges of cut, which flowing is due to insufficient cohesion. This can lead to great problems especially in the ultimate stages of the production, for example due to the pressure sensitive matrix becoming irreversibly stuck to the packaging material. A further unwanted effect of “cold flow” consists in the pressure sensitive adhesive, when applied to the skin, entering more deeply into the pores of the skin than is desired, which makes the later removal of the plaster or the TTS more difficult, or painful.
Pressure-sensitive adhesives based on polyacrylate polymers frequently involve the problem of requiring the addition of adhesive power modulators, e.g. of so-called plasticizers, in order to be able to ensure a sufficient adhesive effect even under the above-described extreme conditions. To this end, the pressure sensitive polyacrylate adhesives must be adjusted to be very soft, with the consequence that it is often unavoidable that residues of adhesive remain on the skin after the plaster has been removed.
Especially in the case of pressure sensitive adhesives containing acidic polyacrylates, further problems result from the fact that they possess a poor tolerance to moisture, which entails drawbacks in respect of adherence to the skin, and from the fact that they possess a chemical affinity to basic active agents. The latter is disadvantageous since as a result of an irreversible acid-base reaction between the acid polyacrylates and the basic active substances, the release and thereby the bioavailability of the pharmaceutical agent in question is reduced.
For this reason, for a pressure-sensitive adhesive to be suitable for use in transdermal therapeutic systems, it should ideally be compatible, in physicochemical respects, with the most varied pharmaceutical active substances and should not enter into unfavourable interactions with those substances.
Furthermore, a pressure sensitive adhesive should possess the following advantageous adhesive properties: it should have a certain minimum tackiness without requiring the addition of a plasticizer. This minimum tackiness should change into an aggressive tackiness only upon exposure to skin moisture, but the adhesive should nevertheless be water-resistant. A further requirement is that after the application has ended, it should be possible to remove the adhesive from the skin without leaving any residues.
In DE 44 29 791 A1 there is described a pressure sensitive adhesive composition containing two polymer components, namely a self-adhesive, carboxyl group-containing polyacrylate polymer and a basic, amino group-containing polymer. In this way, cross-linking is to be brought about by interactions between the acid and the basic groups. Under the influence of skin moisture, these interactions are weakened, which results in a desired increase in tackiness for the duration of the application. However, the initial tackiness of such a pressure sensitive adhesive is very poor, which is why plasticizers have to be added to achieve the required minimum or base tackiness. The added tackifiers can, however, lead to the above-described drawbacks. Since the above described interaction between the acid and the basic groups is reversible under the influence of moisture, there may occur unwanted interactions with the possibly present acid or basic active agents if the adhesive is used in a TTS, this will lead to disadvantageous effects on the release of the active agents to the skin and thereby on their bioavailability.
It has furthermore been proposed to neutralise acid pressure-sensitive polyacrylate adhesives with alkali metal compounds in order to improve their adhesive properties, but only in connection with acid pharmaceutical active substances. By way of the neutralisation of the acid pressure-sensitive polyacrylate adhesives it is intended to achi ve an increase in coherence, improved adhesion to the skin, increased loadability with plasticizing auxiliary substances, as well as increased resistance to moisture. Such pressure sensitive adhesives do, however, have the disadvantage of being little suited as active substance reservoirs for, for instance, hydrolysis-sensitive or chemically unstable pharmaceutical active agents since the slightly alkaline medium of these pressure-sensitive adhesive systems entails the risk of accelerated decomposition, respectively of an increased break-down of the active substances. In addition, neutralised polyacrylate polymers, contrary to expectations, proved in part to be moisture-sensitive and diminishing in their adhesive power, the latter being due to their strong cohesion and the poor flowability associated therewith.
For this reason, in the case of pressure-sensitive adhesive systems based on neutralised polyacrylates, it is necessary to add highly water-binding additives to increase the moisture tolerance. Moreover, it is necessary to use plasticizers to achieve an optimal skin adhesion, or to add an additional pressure-sensitive adhesive layer improving the bond of the system with the skin.